Cell-Mediated Immune Responses
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Cell-mediated immunity combats infections by intracellular microbes; mediated by T lymphocytes
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Elimination of microbes able to live in phagocytic vesicles or in cytoplasm of infected cells is main function of T cell arm of adaptive immunity
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To perform their functions, T lymphocytes have to interact with other cells, which may be phagocytes, infected host cells, or B lymphocytes o Specificity of T cells for peptides displayed by MHC molecules ensures they see and respond only to antigens associated with other cells
Phases of T Cell Responses
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Naïve T lymphocytes constantly recirculate through peripheral lymphoid organs searching for foreign protein antigens; naïve T cells express antigen receptors and other molecules that make up machinery of antigen recognition, but naïve lymphocytes incapable of performing effector functions required for eliminating microbes o Naïve T cells have to differentiate into effector cells; initiated by antigen recognition o Protein antigens of microbes transported from portals of entry of microbes to same peripheral lymphoid organs through which naïve T cells recirculate; there antigens processed and displayed by MHC molecules on dendritic cells o Naïve T cells enter lymph nodes from circulation, and then rapidly move around in nodes, scanning surfaces of dendritic cells for presence of antigen o When T cell recognizes antigen, cell transiently stops moving and initiates activation program o At same time as T cells are seeing antigen, they receive additional signals in form of microbial products or molecules expressed by APCs during innate immune reactions to microbes
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On activation by antigen and other stimuli, antigen-specific T cells begin to secrete cytokines o Some cytokines stimulate proliferation of antigen-specific T cells, resulting in rapid increase in number of antigen-specific lymphocytes (clonal expansion) o Fraction of activate lymphocytes undergo differentiation, which results in conversion of naïve T cells into population of effector T cells to eliminate microbes o Some effector T cells may remain in lymph node, where they function to eradicate infected cells in lymph node or provide signals to B cells that promote antibody responses against microbes o Other effector T cells leave lymphoid organs where they differentiated from naïve T cells, enter circulation, and migrate to any site of infection, where they eradicate infection o Some of progeny of T cells that have proliferated in response to antigen develop into memory T cells
(long-lived and functionally inactive and circulate for months or years, ready to rapidly respond to repeat exposures to same microbe) o As effector T cells eliminate infectious agent, stimuli that triggered T cell expansion and differentiation also eliminated; as result, greatly expanded clone of antigen-specific lymphocytes dies, thereby returning system to basal resting state
Antigen Recognition and Costimulation
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Initiation of T cell responses requires multiple receptors on T cells recognizing ligands on APCs; TCR recognizes
MHC-associated peptide antigens, CD4 or CD8 coreceptors recognize MHC molecules, adhesion molecules strengthen binding of T cells to APCs, and receptors for costimulators recognize second signals provided by APCs o Molecules other than antigen receptors involved in T cell responses to antigens called accessory molecules of T lymphocytes; accessory molecules invariant among all T cells
 Accessory molecules involved in signaling and adhesion
 Different accessory molecules bind to different ligands and each interaction plays distinct and complementary role in process of T cell activation
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TCR and CD4 or CD8 coreceptor together recognize complex of peptide antigens and MHC molecules on APCs, and this recognition provides first or initiating signal for T cell activation o When protein antigens are ingested by APCs from extracellular milieu into vesicles, these antigens processed into peptides that are displayed by class II MHC molecules o Protein antigens present in cytoplasm processed into peptides that are displayed by class I MHC molecules o TCR of peptide antigen-specific T cell recognizes displayed peptide and simultaneously recognizes residues of MHC molecule that are located around peptide-biding cleft

o CD4 or CD8 function with TCR to bind MHC molecules o At time when TCR is recognizing peptide-MHC complex, CD4 or CD8 recognizes class II or class I MHC molecule at site separate from peptide-binding cleft
 CD4+ T cells (function as cytokine-producing helper cells) recognize microbial antigens ingested from extracellular milieu and are displayed by class II MHC molecules
 CD8+ T cells (function as CTLs) recognize peptides derived from cytoplasmic microbes displayed by class I MHC molecules
 Specificity of CD4 and CD8 for different classes of MHC molecules and distinct pathways of processing of vesicular and cytosolic antigens ensure correct T cells respond to different microbes
 2+ TCRs and coreceptors need to be engaged simultaneously to initiate T cell response because only if multiple TCRs and coreceptors are brought together can appropriate biochemical signaling cascades be activated
 Only one T cell can respond only if it encounters array of peptide-MHC complexes on APC
 Each T cell needs to engage antigen (i.e., MHC-peptide complexes) for long period (at least several minutes) or multiple times to generate enough biochemical signals to initiate response; then T cell begins activation program o Biochemical signals that lead to T cell activation triggered by set of proteins that are linked to TCR to form TCR complex and by CD4 or CD8 coreceptor
 Different T cells must possess antigen receptors that are variable enough to recognize diverse antigens and other molecules that serve conserved signaling roles and don’t need to be variable
 TCR recognizes antigens, but not able to transmit biochemical signals to interior of cell; TCR noncovalently associated with complex of 3 proteins (CD3) and homodimer of signaling protein
(ζ chain); TCR, CD3, and ζ chain make up TCR complex
 In TCR complex, function of antigen recognition performed by variable TCR α and β chains, whereas conserved signaling function performed by attached CD3 and ζ proteins o T cells can be activated experimentally by molecules that bind to TCRs of many or all clones of T cels, regardless of peptide-MHC specificity of TCR; polyclonal activators include antibodies specific for TCR or associated CD3 proteins, polymeric carb-binding proteins (such as phytohemagglutinin), and certain microbial proteins (superantigens)
 Polyclonal activators often used as experimental tools to study T cell responses and in clinical settings to test for T cell function or prepare metaphase spreads for chromosomal analysis
 Microbial superantigens may cause serious disease by inducing excessive cytokine release from many T cells
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Adhesion molecules on T cells recognize their ligands on APCs and stabilize binding of T cells to APCs o Most TCRs bind peptide-MHC complexes for which they are specific with low affinity
 T cells positively selected for weak recognition of self antigens and ability to recognize foreign microbial peptides is fortuitous and not predetermined o To induce productive response, binding of T cells to APCs must be stabilized for sufficiently long period that necessary signaling threshold is achieved
 Stabilization function performed by adhesion molecules on T cells whose ligands are expressed on APCs; most important are integrins
 Major T cell integrin involved in binding to APCs is LFA-1 (leukocyte function-associated antigen), whose ligand on APCs is ICAM-1 (intercellular adhesion molecule) o Integrins play important role in enhancing T cell responses to microbial antigens
 On resting naïve T cells, LFA-1 integrin in low-affinity state; if T cell exposed to chemokines produced as part of innate immune response to infection, that T cell’s LFA-1 molecules converted to high-affinity state and cluster together in minutes so T cells bind strongly to APCs
 Antigen recognition by T cell increases affinity of that cell’s LFA-1; once T cell sees antigen, it increases strength of its binding to APC presenting that antigen, providing positive feedback loop
 Integrins also play important role in directing migration of effector T cells from circulation to sites of infection

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Full activation of T cells dependent on recognition of costimulators (second signals) on APCs o Best-defined costimulators for T cells are B7-1 (CD80) and B7-2 (CD86), both of which expressed on APCs and whose expression greatly increased when APC encounters microbes
 B7 proteins recognized by receptor (CD28) expressed on virtually all T cells
 Signals from CD28 on T cells binding to B7 on APCs work together with signals generated by binding of TCR and coreceptor to peptide-MHC complexes on same APCs
 CD28-mediated signaling essential for initiating responses of naïve T cells; in absence of Cd28-B7 interactions, engagement of TCR alone unable to activate T cells o Requirement for costimulation ensures that naïve T lymphocytes activated fully by microbial antigens, and not by harmless foreign substances because microbes stimulate expression of B7 costimulators o CD40 ligand (CD154) on T cells and CD40 on APCs – don’t directly enhance T cell activation; CD40L expressed on antigen-stimulated T cell binds to CD40 on APCs and activates APCs to express more B7 costimulators and secrete cytokines (such as IL-12) that enhance T cell differentiation
 CD40L-CD40 interaction promotes T cell activation by making APCs better at stimulating T cells o Protein antigens, such as those used in vaccines, fail to elicit T cell-dependent immune responses unless these antigens administered with substances that activate APCs, including dendritic cells and macrophages (possible B cells); these called adjuvants and function mainly by inducing expression of costimulators on APCs and stimulating APCs to secrete cytokines that activate T cells
 Most adjuvants products of microbes (e.g., killed mycobacteria) or substances that mimic microbes; adjuvants convert inert protein antigens into mimics of pathogenic microbes
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Enhancing expression of costimulators may be useful for stimulating T cell responses (e.g., against tumors), and blocking costimulators may be strategy for inhibiting unwanted responses o Agents that block B7:CD28 used in treatment of RA and other inflammatory diseases o Antibodies that block CD40:CD40L interactions being tested in inflammatory diseases and transplant recipients to reduce or prevent graft rejection
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Proteins homologous to CD28 critical for limiting and terminating immune responses o Different members of CD28 family involved in activating and inhibiting T cells o CTLA-4 recognize B7 on APCs; involved in inhibiting responses to some tumors o PD-1 recognizes different but related ligands on many cell types; inhibits responses to some infections and allows infections to become chronic o Both CTLA-4 and PD-1 induced in activated T cells, and genetic deletion of molecules results in excessive lymphocyte expansion and autoimmune disease
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Activation of CD8+ T cells stimulated by recognition of class I MHC-associated peptides and requires costimulation and/or helper T cells o Initiation of activation of CD8+ T cells often requires that cytoplasmic antigen from one cell has to be cross-presented by dendritic cells o Differentiation into CTLs may require concomitant activation of CD4+ helper T cells
 When virus-infected cells ingested by host dendritic cells and viral antigens cross-presented by
APCs, same APC may present antigens from cytosol in complexes with class I MHC molecules and from vesicles in complex with class II MHC molecules
 Both CD8+ T cells and CD4+ T cells specific for viral antigens activated near one another
 CD4+ T cells may produce cytokines or membrane molecules that help activate CD8+ T cells
 Requirement for helper T cells in CD8+ T cell responses likely explanation for defective CTL responses to many viruses in patients infected with HIV, which kills CD4+ but not CD8+ cells o CTL responses to some viruses don’t appear to require help from CD4+ T cells
Biochemical Pathways of T Cell Activation
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On recognition of antigens and costimulators, T cells express proteins involved in proliferation, differentiation, and effector functions of cells o Naïve T cells that haven’t encountered antigen (resting cells) have low level of protein synthesis o Within minutes of antigen recognition, new gene transcription and protein synthesis seen in activated T
 cells
Biochemical pathways that link antigen recognition with T cell responses consist of activation of enzymes, recruitment of adaptor proteins, and production of active transcription factors

o Biochemical pathways initiated by physically bringing together multiple TCRs (cross-linking) and they occur at or near TCR complexes o Multiple TCRs and coreceptors brought together when they bind MHC-peptide complexes that are near one another on surface of APCs o There is orderly redistribution of other proteins in both APC and T cell membranes at point of cell-to-cell contact, such that TCR complex, CD4/CD8 coreceptors, and CD28 coalesce to center and integrins move to form peripheral ring
 Responsible for optimal induction of activating signals in T cell o Immunologic synapse – region of contact between APC and T cell, including redistributed membrane proteins; may secrete some effector molecules and cytokines, ensuring they don’t diffuse away but are targeted to APC
 Enzymes that serve to degrade or inhibit signaling molecules recruited to synapse o Clustering of CD4 or CD8 coreceptors activates tyrosine kinase (Lck) that is noncovalently attached to cytoplasmic tails of coreceptors
 Several transmembrane signaling proteins associated with TCR, including CD3 and ζ chains, which both contain tyrosine-rich motifs (immunoreceptor tyrosine-based activation motifs or
ITAMs) critical for signaling
 Lck carried near TCR complex by CD4 or CD8 molecules; phosphorylates tyrosine residues contained within ITAMs of ζ and CD3 proteins
 Phosphorylated ITAMs of ζ chain become docking sites for tyrosine kinase (ZAP-70) which also is phosphorylated by Lck and thereby made enzymatically active
 Active ZAP-70 phosphorylates various adapter proteins and enzymes, which assemble near TCR complex and mediate additional signaling events
 Major signaling pathways linked to ζ chain phosphorylation and ZAP-70 are calcium-NFAT pathway, Ras/Rac-MAP kinase pathway, and PKCθ-NF-κB pathway
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Nuclear factor of activated T cells (NFAT) – transcription factor whose activation is dependent on Ca 2+ ; calcium-
NFAT pathway initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ), which catalyzes hydrolysis of PM inositol phospholipid (phosphatidylinositol 4,5-bisphosphate or PIP
2
) o One byproduct of PLCγ-mediated PIP
2
breakdown (inositol 1,4,5-trisphosphate or IP
3
) stimulates release of Ca 2+ from ER, thereby raising cytoplasmic Ca 2+ concentration o In response to elevated Ca 2+ , PM calcium channel opens, leading to influx of extracellular Ca 2+ into cell, which sustains elevated Ca 2+ for hours o Cytoplasmic Ca 2+ binds to calmodulin; Ca 2+ -calmodulin complex activates phosphatase (calcineurin), which removes phosphates from NFAT, which resides in cytoplasm
 Once dephosphorylated, NFAT able to migrate into nucleus, where it binds to and activates promoters of several genes, including genes encoding T cell growth factor IL-2 and components of IL-2 receptor
 Cyclosporine binds to and inhibits activity of calcineurin and thus inhibits production of cytokines by T cells; widely used as immunosuppressive drug to prevent graft rejection
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Ras/Rac-MAP kinase pathways include GTP binding Ras and Rac proteins, several adaptor proteins, and cascade
 of enzymes that eventually activate one of family of MAP (mitogen-activated protein) kinases o Pathways initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at PM, leading to recruitment of Ras or Rac, and their activation by exchange of bound GDP with GTP o Ras·GTP and Rac·GTP initiate different enzyme cascades, leading to activation of distinct MAP kinases o Terminal MAP kinases in pathways (extracellular signal-related kinase or ERK and c-Jun amino-terminal kinase or JNK) promote expression of protein (c-Fos) and phosphorylation of c-Jun o c-Fos and phosphorylated c-Jun combine to form transcription factor AP-1, which enhances transcription of several T cell genes
Third major pathway involved in TCR signaling consists of activation of θ isoform of serine-threonine kinase
(PKC) and activation of transcription factor NF-κB o PKC activated by diacylglycerol, which is generated by phospholipase C-mediated hydrolysis of membrane inositol lipids o PKCθ acts via adaptor proteins recruited to TCR complex to activate NF-κB

o NF-κB exists in cytoplasm of resting T cells in inactive form, bound to inhibitor called IκB o TCR-induced signals, downstream of PKCθ, activate kinase that phosphorylates IκB and targets it for destruction; as result, NF- κB released and moves to nucleus, where it promotes transcription of several genes
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Fourth pathway involves lipid kinase phosphatidylinositol-3 (PI-3) kinase, which phosphorylates membrane PIP
2 to generate PIP
3 o PIP
3
ultimately activates serine-threonine kinase (Akt), which has many roles, including stimulating expression of anti-apoptotic proteins and thus promoting survival of antigen-stimulated T cells o PI-3 kinase/Akt pathway triggered by TCR, CD28, and IL-2 receptors
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Various transcription factors (NFAT, AP-1, and NF-κB) stimulate transcription and subsequent production of cytokines, cytokine recpetors, cell cycle inducers, and effector molecules such as CD40L o All signals initiated by antigen recognition because binding of TCR and coreceptors to antigen (peptide-
MHC complexes) necessary to assemble signaling molecules and initiate enzymatic activity
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Biochemical signals transduced by CD28 on binding to B7 costimulators less defined than TCR-triggered signals o Likely that CD28 engagement amplifies some TCR signals and initiates distinct set of signals that complement TCR signals
Functional Responses of T Lymphocytes to Antigen and Costimulation
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Recognition of antigen and costimulators by T cells initiates orchestrated set of responses that culminate in expansion of antigen-specific clones of lymphocytes and differentiation of naïve T cells into effector cells and memory cells o Many of responses of T cells mediated by cytokines secreted by T cells and act on T cells themselves and on many other cells involved in immune defenses
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In response to antigen and costimulators, T lymphocytes, especially CD4+ T cells, rapidly secrete several different cytokines that have diverse activities o Cytokines – large group of proteins that function as mediators of immunity and inflammation; secreted by T cells; different cytokines have distinct activities and play different roles in immune responses o First cytokine produced by CD4+ T cells (1-2 hours after activation) is IL-2
 Activation rapidly enhances ability of T cells to bind and respond to IL-2 by increasing expression of IL-2 receptor
 High-affinity receptor for IL-2 is 3-chain molecule
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Naïve T cells express 2 signaling chains of receptor but don’t express the chain that enables receptor to bind IL-2 with high affinity
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Within hours after activation by antigens and costimulators, T cells produce 3 rd chain of receptor and complete IL-2 receptor is able to bind IL-2 strongly
 IL-2 produced by antigen-stimulated T cells preferentially binds to and acts on same T cells; principal actions are stimulate survival and proliferation of T cells
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Essential for maintenance of regulatory T cells and thus controlling immune responses
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Stimulates T cells to enter cell cycle and begin to divide, resulting in increase in number of antigen-specific T cells o Differentiated effector CD4+ T cells produce many other cytokines o CD8+ T lymphocytes that recognize antigen and costimulators don’t secrete large amounts of IL-2, but they proliferate prodigiously during immune responses; possible that antigen recognition and costimulation able to drive proliferation of CD8+ T cells without requirement of IL-2
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Within 1-2 days after activation, T lymphocytes begin to proliferate, resulting in expansion of antigen-specific clones; expansion helps adaptive immune response keep pace with rapidly dividing microbes and provides large pool of antigen-specific lymphocytes from which effector cells can be generated to combat infection o Before infection, frequency of CD8+ T cells specific for any one microbial protein antigen about 1 in 10 5 of 10 6 lymphocytes in body; at peak of some viral infections (may be within a week of infection) as many as 10-20% of all lymphocytes in lymphoid organs may be specific for that virus (increased 100,000x)
 Estimated doubling time is 6 hours o Enormous expansion of T cells specific for microbe not accompanied by detectable increase in bystander cells that don’t recognize that microbe

o Even in infections with complex microbes that contain many protein antigens, majority of expanded clones specific for only a few, and often less than 5, immunodominant peptides on that microbe o Expansion of CD4+ T cells only about 100-1000x o Many CTLs needed to kill large numbers of infected cells; each CD4+ effector cell secretes cytokines that activate many other effector cells, so relatively small number needed
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Progeny of antigen-stimulated proliferating T cells begin to differentiate into effector cells; differentiation is result of changes in gene expression (e.g., activation of genes encoding cytokines or cytotoxic proteins) o Begins in concert with clonal expansion, and differentiated effector cells appear in 3-4 days of exposure to microbes o Differentiated effector cells leave peripheral lymphoid organs and migrate to site of infection, where they encounter microbial antigens that stimulated their development o On recognition of antigen, effector cells respond in their way
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CD4+ helper T cells differentiate into effector cells that respond to antigen by producing surface molecules and cytokines that function to activate phagocytes and B lymphocytes o Most important cell surface protein is CD40L; gene transcribed in response to antigen recognition and costimulation, and result is CD40L expressed on helper T cells after activation
 CD40L binds to its CD40, which is expressed mainly on macrophages, B lymphocytes, and dendritic cells
 Engagement of CD40 activates these cells
 Interaction of CD40L on T cells with CD40 on dendritic cells stimulates expression of costimulators on APCs and production of T cell-activating cytokines, thus providing positive feedback (amplification) mechanism for APC-induced T cell activation
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Helminthic parasites too large to be phagocytosed and immune response to helminths dominated by production of IgE antibodies and activation of eosinophils o IgE antibody binds to helminths, and eosinophils and other leukocytes destroy the helminthes
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CD4+ helper T cells may differentiate into subsets of effector cells that produce distinct sets of cytokines and perform different functions o T
H
1 and T
H
2 cells distinguished by cytokines they produce and cytokine receptors and adhesion molecules they express o T
H
17 cells express cytokine IL-17 o Many activated CD4+ T cells produce various mixtures of cytokines and therefore can’t be readily classified into one of those subsets
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T
H
1 cells stimulate phagocyte-mediated ingestion and killing of microbes; most important cytokine produced by
T
H
1 cells is interferon-γ (IFN-γ), which interferes with viral infection o IFN-γ is potent activator of macropahges (type I IFNs much more potent anti-viral cytokines than IFN-γ) o IFN-γ stimulates production of antibody isotypes that promote phagocytosis of microbes because antibodies bind directly to phagocyte Fc receptors, and they activate complement, generating products that bind to phagocyte complement receptors o IFN-γ also stimulates expression of class II MHC molecules and B7 costimulators on macrophages and dendritic cells; may serve to amplify T cell responses
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T
H
2 cells stimulate phagocyte-independent, eosinophil-mediated immunity (especially effective against helminthic parasites) o T
H
2 cells produce IL-4 (stimulates production of IgE antibodies) and IL-5 (activates eosinophils) o IgE activates mast cells and binds to eosinophils; IgE-dependent mast cell-mediated and eosinophilmediated reactions important in killing helminthic parasites o Some cytokines produced by T
H
2 cells (IL-4 and IL-13) promote expulsion of parasites from mucosal organs and inhibit entry of microbes by stimulating mucus secretion
 Sometimes called barrier immunity because it blocks entry of microbes at mucosal barriers o Cytokines of T
H
2 cells also activate macrophages; T
H
2-mediated macrophage activation enhances synthesis of ECM proteins involved in tissue repair (alternative macrophage activation) o IL-4, IL-10, and IL-13 inhibit microbicidal activities of macrophages and thus suppress T
H
1 cell-mediated immunity; efficacy of cell-mediated immune responses against microbe determined by balance between activation of T
H
1 cells and T
H
2 cells

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T
H
17 cells secrete cytokines IL-17 and IL-22 and are principal mediators of inflammation in number of immunologic reactions; implicated in MS, inflammatory bowel disease, and RA o Studies suggest T
H
17 cells also involved in defense against some bacterial and fungal infections
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Development of T
H
1, T
H
2, and T
H
17 subsets regulated by stimuli that naïve CD4+ T cells receive when they encounter microbial antigens o T
H
1 differentiation driven by combination of IL-12 and IFN-γ
 In response to many bacteria and viruses, dendritic cells and macropahges produce IL-12 and NK cells produce IFN-γ
 When naïve T cells recognize antigens of these microbes, T cells also exposed to these cytokines, which activate transcription factors that promote differentiation of T cells to T
H
1 subset
 T
H
1 cells produce IFN-γ, which activates macrophages to kill microbes and promotes more T
H
1 development o Development of T
H
2 cells stimulated by IL-4; main source of IL-4 is T
H
2 cells
 If infectious microbe doesn’t elicit IL-12 production by APCs, T cells themselves produce IL-4
 Helminths may activate cells of mast cell lineage to secrete IL-4
 In antigen-stimulated T cells, IL-4 activates transcription factors that promote differentiation to
T
H
2 subset o Development and maintenance of T
H
17 cells require inflammatory cytokines such as IL-6 and IL-1
(produced by macrophages and dendritic cells), IL-23 (related to IL-12, made by same cells), and TGF-β o Once any of these populations develops from antigen-stimulated helper T cells, it produces cytokines that enhance differentiation of T cells toward its own subset and inhibits development of other populations (cross-regulation)
 May lead to increasing polarization of response toward one population
 Some differentiated CD4+ T cells can convert from one subset into another under certain conditions
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CD8+ T lymphocytes activated by antigen and costimulators differentiate into CTLs able to kill infected cells expressing the antigen; effector CTLs secrete proteins that create pores in membranes of infected cells and induce DNA fragmentation and apoptotic death of these cells o Differentiation of naïve CD8+ T cells into effector CTLs accompanied by synthesis of molecules that kill infected cells
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Fraction of antigen-activated T lymphocytes differentiate into long-lived memory cells; memory cells found in lymphoid organs, mucosal tissues, and circulation o Memory T cell require signals delivered by certain cytokines, including IL-7, in order to stay alive o Memory cells don’t continue to produce cytokines or kill infected cells, but may do so rapidly on encountering antigen they recognize o Subset of memory T cells (central memory cells) populate lymphoid organs and are responsible for rapid clonal expansion after re-exposure to antigen o Effector memory cells localize in mucosal tissue and mediate rapid effector functions on reintroduction of antigen to these sites
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During immune response, survival and proliferation of T cells maintained by antigen, costimulatory signals from
CD28, and cytokines such as IL-2 o Once infection cleared and stimuli for lymphocyte activation disappear, many cells that had proliferated in response to antigen deprived of survival signals and begin to die by apoptosis o Response subsides within 1-2 weeks after infection eradicated
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Numerous mechanisms ensure generation of useful T cell response, despite several obstacles o Naïve T cells have to find antigen; APCs capture antigen and concentrate it in specialized lymphoid organs and regions through which naïve T cells recirculate o Correct type of T lymphocytes must respond to antigens from extracellular and intracellular compartments; selectivity determined by specificity of CD4 and CD8 coreceptors for class II and class I
MHC molecules and by segregation of extracellular (vesicular – by class II MHC molecules) and intracellular (cytoplasmic – by class I MHC molecules) protein antigens for display o T cells must interact with antigen-bearing APCs long enough to be activated; accomplished by adhesion molecules that stabilize T cell binding to APCs

o T cells should respond to microbial antigens but not harmless proteins; preference maintained because
T cell activation requires costimulators induced on APCs by microbes o Antigen recognition by small number of T cells must lead to response large enough to be effective
 Accomplished by several amplification mechanisms induced by microbes and activated T cells themselves and lead to enhanced T cell activation